DESCRIPTION: Opioids are the most powerful analgesics currently used for the treatment of pain, but repeated administration induces tolerance which significantly decreases the analgesic effect of opioids. The general goal of this project is to elucidate the contribution of different types of opioid receptors to the mechanisms of opioid tolerance. The nucleus raphe magnus (NRM) in the medulla is critically implicated in opioid analgesia through its direct projections to the spinal dorsal horn, the first relay for pain transmission. Our previous studies have shown how agonists of the mu-opioid receptor act in the NRM to produce analgesia. Recently we have demonstrated the neural mechanism by which kappa-opioid receptor agonists in the NRM oppose the mu-receptor-mediated analgesia. The hypothesis for the current project is that opioid tolerance results from a functional reduction of the mu-receptor mediated actions and an up-regulation of other endogenous anti-mu systems such as the kappa-receptor system and the GABA transmission system, a major target of inhibitory actions of analgesic opioids. Using the NRM as a model system, the proposed studies are designed to determine the functional changes both in the synaptic properties of NRM neurons and in the actions mediated by mu- and kappa-receptors in opioid-tolerant rats versus opioid-naive rats. Both intracellular/whole-cell patch clamp recording in NRM slices in vitro and NRM microinjection in freely-moving rats in vivo will be used to characterize the cellular mechanisms of the adaptive changes and their behavioral significance in animals. This research will significantly expand our knowledge of the neural mechanisms for opioid tolerance and contribute to our efforts to improve the treatment for chronic pain and other chronic opioid-related problems.